Mechanisms of cerebral infarcts and brain oxygen utilization in anemia

项目总结 而脑氧输送取决于脑血流量(CBF；毫升血液/100克组织/分钟)和 血液含氧量，人们越来越认识到，毛细血管通过时间本身也可以 影响组织氧摄取，即使在CBF正常或升高的情况下也是如此。对于具有以下特征的个人 毛细血管血流速度加快的贫血，可能是由于充血和 大脑自动调节，减少毛细血管通过时间可以减少组织氧气的时间 卸货。为异常下的非均质毛细管流提供了令人信服的证据 包括急性缺血性卒中、创伤性脑梗塞扩大在内的多种情况下的氧输送 伤害和阿尔茨海默氏症。在镰状细胞性贫血(SCA)中，我们观察到快速毛细血管传输， 在动脉自旋标记(ASL)CBF加权MRI上可见，在超过50%的成人和儿童中存在。 我们在已发表的工作和154名患有SCA的成人和儿童的初步数据中表明， 脑硬膜静脉窦内高信号的ASL信号与动脉抬高直接相关 血流速度、增加的CBF和还原的氧提取分数(OEF；耗氧量与氧气的比率 提供)，这种效果可能会减少以下输血疗法，改善氧气输送到 组织。这些发现表明ASL图像上的静脉高信号可能代表着 氧交换效率的毛细水平扰动。我们最具影响力的发现之一就是 初步工作是，我们观察到快速的毛细血管水平的动-静脉传输与 氧代谢降低，这表明这些转运时间可能提供了 年龄组脑梗塞风险大于50%的SCA患者的脑缺血 30岁，但往往缺乏传统的中风危险因素。在这里，我们建议改进神经成像 评估动-静脉转运以允许稳健、定量地测量毛细血管转运时间的方法 非侵入性的活体实验，并随后测试有关脑氧利用的基本假设 在有脑梗塞的贫血患者和没有脑梗塞的贫血患者中。目的(1)：应用创新的ASL MRI方法和时间 健康对照组和SCA受试者颅内主要动脉和硬脑膜窦的回归分析。 目的(2)：量化SCA患者用血治疗前后的脑毛细血管通过时间 输血以了解血红蛋白的增加如何与脑氧提取的改善平行。 目的(3)：检验SCA患者动静脉转运时间缩短的假设。 而不是没有脑梗塞。短期目标是利用非侵入性成像方法来了解 贫血时氧利用和神经血管功能障碍的机制。长期目标是 使用此信息对贫血患者进行分类，以进行个性化的中风预防治疗，如 以及客观地量化这些疗法对大脑健康的影响。

PROJECT SUMMARY While cerebral oxygen delivery depends on the cerebral blood flow (CBF; ml blood/100g tissue/minute) and blood oxygen content, it is becoming increasingly recognized that blood capillary transit time itself can also influence tissue oxygen extraction, even in the presence of normal or elevated CBF. In individuals with anemia where accelerated capillary flow velocities may be present as a result of hyperemia and cerebral autoregulation, reduced capillary transit time can lead to reduced times for tissue oxygen offloading. Compelling evidence has been provided for heterogeneous capillary flow underlying abnormal oxygen delivery in multiple conditions including expansion of infarcts in acute ischemic stroke, traumatic brain injury, and Alzheimer's disease. In sickle cell anemia (SCA), we have observed that rapid capillary transit, visible on arterial spin labeling (ASL) CBF-weighted MRI, is present in more than 50% of adults and children. We have shown in published work and preliminary data from 154 adults and children with SCA that hyperintense ASL signal within cerebral dural venous sinuses is directly associated with elevated arterial velocities, elevated CBF, and reduced oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), and that this effect may reduce following transfusion therapies that improve oxygen delivery to tissue. These findings indicate that venous hyperintense signal on ASL images may represent a marker of capillary-level disturbances in oxygen exchange efficiency. One of the most impactful findings of our preliminary work is that we have observed that rapid capillary-level arterio-venous transit is associated with reduced oxygen metabolism, suggesting that these transit times may provide a biomarker of cerebral ischemia in individuals with SCA who have greater than a 50% risk of cerebral infarcts by age 30 years, yet often lack conventional stroke risk factors. Here, we propose to refine neuroimaging methods for evaluating arterio-venous transit to allow for robust, quantitative measures of capillary transit time non-invasively in vivo, and subsequently to test fundamental hypotheses regarding cerebral oxygen utilization in anemic individuals with vs. without infarcts. Aim (1): To apply innovative ASL MRI methods and time regression analyses over major intracranial arteries and dural sinuses in healthy control and SCA participants. Aim (2): To quantify cerebral capillary transit time in SCA participants before and after treatment with blood transfusion to understand how increases in hemoglobin parallel an improvement in brain oxygen extraction. Aim (3): To test the hypothesis that arterio-venous transit times are reduced in individuals with SCA with versus without infarcts. The short-term goal is to utilize non-invasive imaging approaches to understand mechanisms of oxygen utilization and neurovascular dysfunction in anemia. The long-term goal is to use this information to triage individuals with anemia for personalized stroke prevention therapies, as well as to objectively quantify the impact of these therapies on brain health.